Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease

Myung Jun Lee, Kyoungjune Pak, Jong Hun Kim, Yun Joong Kim, Jeehee Yoon, Jinwoo Lee, Chul Hyoung Lyoo, Hyung Jun Park, Jae Hyeok Lee, Na Yeon Jung

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.

Original languageEnglish
Pages (from-to)e665-e674
JournalNeurology
Volume93
Issue number7
DOIs
Publication statusPublished - 2019 Aug 13

Fingerprint

Corpus Striatum
Parkinson Disease
Nortropanes
Single Nucleotide Polymorphism
Disease Progression
Databases
Caudate Nucleus
Putamen
Single-Photon Emission-Computed Tomography
Age of Onset
Gene Frequency
Linear Models

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Lee, M. J., Pak, K., Kim, J. H., Kim, Y. J., Yoon, J., Lee, J., ... Jung, N. Y. (2019). Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease. Neurology, 93(7), e665-e674. https://doi.org/10.1212/WNL.0000000000007939
Lee, Myung Jun ; Pak, Kyoungjune ; Kim, Jong Hun ; Kim, Yun Joong ; Yoon, Jeehee ; Lee, Jinwoo ; Lyoo, Chul Hyoung ; Park, Hyung Jun ; Lee, Jae Hyeok ; Jung, Na Yeon. / Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease. In: Neurology. 2019 ; Vol. 93, No. 7. pp. e665-e674.
@article{f3a5d43c59074cfab6910fe665ea9494,
title = "Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease",
abstract = "OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.",
author = "Lee, {Myung Jun} and Kyoungjune Pak and Kim, {Jong Hun} and Kim, {Yun Joong} and Jeehee Yoon and Jinwoo Lee and Lyoo, {Chul Hyoung} and Park, {Hyung Jun} and Lee, {Jae Hyeok} and Jung, {Na Yeon}",
year = "2019",
month = "8",
day = "13",
doi = "10.1212/WNL.0000000000007939",
language = "English",
volume = "93",
pages = "e665--e674",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

Lee, MJ, Pak, K, Kim, JH, Kim, YJ, Yoon, J, Lee, J, Lyoo, CH, Park, HJ, Lee, JH & Jung, NY 2019, 'Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease', Neurology, vol. 93, no. 7, pp. e665-e674. https://doi.org/10.1212/WNL.0000000000007939

Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease. / Lee, Myung Jun; Pak, Kyoungjune; Kim, Jong Hun; Kim, Yun Joong; Yoon, Jeehee; Lee, Jinwoo; Lyoo, Chul Hyoung; Park, Hyung Jun; Lee, Jae Hyeok; Jung, Na Yeon.

In: Neurology, Vol. 93, No. 7, 13.08.2019, p. e665-e674.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease

AU - Lee, Myung Jun

AU - Pak, Kyoungjune

AU - Kim, Jong Hun

AU - Kim, Yun Joong

AU - Yoon, Jeehee

AU - Lee, Jinwoo

AU - Lyoo, Chul Hyoung

AU - Park, Hyung Jun

AU - Lee, Jae Hyeok

AU - Jung, Na Yeon

PY - 2019/8/13

Y1 - 2019/8/13

N2 - OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.

AB - OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.

UR - http://www.scopus.com/inward/record.url?scp=85071355958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071355958&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000007939

DO - 10.1212/WNL.0000000000007939

M3 - Article

C2 - 31289143

AN - SCOPUS:85071355958

VL - 93

SP - e665-e674

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 7

ER -